The exozyme model: a continuum of functionally distinct complexes.

Abstract

Exosome complexes are composed of 10 to 11 subunits and are involved in multiple facets of 3' → 5' RNA processing and turnover. The current paradigm stipulates that a uniform, stoichiometric core exosome, composed of single copies of each subunit, carries out all RNA metabolic functions in vivo. While core composition is well established in vitro, available genetic, cell biological, proteomic, and transcriptomic data raise questions about whether individual subunits contribute to RNA metabolic functions exclusively within the complex. Here, we recount the current understanding of the core exosome model and show predictions of the core model that are not satisfied by the available evidence. To resolve this discrepancy, we propose the exozyme hypothesis, a novel model stipulating that while exosome subunits can and do carry out certain functions within the core, subsets of exosome subunits and cofactors also assemble into a continuum of compositionally distinct complexes--exozymes--with different RNA specificities. The exozyme model is consistent with all published data and provides a new framework for understanding the general mechanisms and regulation of RNA processing and turnover.

The functions of the exosome complexes. The functions attributed to the complex are listed in the leftmost column. Exosome subunits were tested and found to be required (yellow boxes) or not required (red boxes). Orange boxes indicate conflicting data in separate studies; asterisks indicate that different degradation and/or processing intermediates accumulated in those subunits. Two asterisks indicate that the subunit alone was sufficient to perform the function in vitro. A complete expanded function table and citation index is included in Supplemental Tables S1 and S2.

TAP profiles of exosome subunits in Sc. The grid shows the subunits co-purifying with each TAP tagged exosome subunit. Yellow boxes indicate the subunit was recovered in the Gavin studies (, ); blue boxes indicate the subunit was recovered in the Krogan studies (, ); green boxes indicate the subunit was recovered in both studies; and red boxes indicate the subunit was not recovered in either study. All co-purifying proteins are listed in Supplemental Table S3.